Zhang Qian, Liu Guoping, Liu Jibin, Yang Mu, Fu Juan, Liu Guodi, Li Dehua, Gu Zhangjie, Zhang Linsong, Pan Yingjiao, Cui Xingbing, Wang Lu, Zhang Lixin, Tian Xiaoli
Shanghai Yihao Biological Technology, Co., Ltd., Shanghai 200231, China.
Department of General Surgery, Changhai Hospital, Shanghai 200433, China.
Mol Ther Oncolytics. 2021 Feb 24;20:556-568. doi: 10.1016/j.omto.2021.02.013. eCollection 2021 Mar 26.
Since the approval of chimeric antigen receptor (CAR) T cell therapy targeting CD19 by the FDA, CAR-T cell therapy has received increasing attention as a new method for targeting tumors. Although CAR-T cell therapy has a good effect against hematological malignancies, it has been less effective against solid tumors. In the present study, we selected mesothelin (MSLN/MESO) as a target for CAR-T cells because it is highly expressed by solid tumors but only expressed at low levels by normal tissues. We engineered a third generation MSLN-CAR comprising a single-chain variable fragment (scFv) targeting MSLN (MSLN-scFv), a CD8 transmembrane domain, the costimulatory domains from CD28 and 4-1BB, and the activating domain CD3ζ. , MSLN-CAR-T cells killed various solid tumor cell lines, demonstrating that it could specifically kill MSLN-positive cells and release cytokines. , we investigated the effects of MSLN-CAR-T cell therapy against ovarian, breast, and colorectal cancer cell-line-derived xenografts (CDX) and MSLN-positive colorectal and gastric cancer patient-derived xenografts (PDX). MSLN-CAR decreased the growth of MSLN-positive tumors concomitant with significantly increased T cells and cytokine levels compared to the control group. These results indicated that modified MSLN-CAR-T cells could be a promising therapeutic approach for solid tumors.
自美国食品药品监督管理局（FDA）批准靶向CD19的嵌合抗原受体（CAR）T细胞疗法以来，CAR-T细胞疗法作为一种靶向肿瘤的新方法受到越来越多的关注。尽管CAR-T细胞疗法对血液系统恶性肿瘤有良好疗效，但对实体瘤的疗效较差。在本研究中，我们选择间皮素（MSLN/MESO）作为CAR-T细胞的靶点，因为它在实体瘤中高表达，而在正常组织中仅低水平表达。我们构建了第三代MSLN-CAR，其包含靶向MSLN的单链可变片段（scFv）（MSLN-scFv）、CD8跨膜结构域、来自CD28和4-1BB的共刺激结构域以及激活结构域CD3ζ。MSLN-CAR-T细胞杀死了各种实体瘤细胞系，表明它可以特异性杀死MSLN阳性细胞并释放细胞因子。我们研究了MSLN-CAR-T细胞疗法对卵巢癌、乳腺癌和结直肠癌细胞系来源的异种移植瘤（CDX）以及MSLN阳性的结直肠癌和胃癌患者来源的异种移植瘤（PDX）的影响。与对照组相比，MSLN-CAR降低了MSLN阳性肿瘤的生长，同时T细胞和细胞因子水平显著增加。这些结果表明，经改造的MSLN-CAR-T细胞可能是一种有前途的实体瘤治疗方法。
